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WO2018154101A1 - Formes cristallines du dérivé 4-pyrimidinesulfamide aprocitentan - Google Patents

Formes cristallines du dérivé 4-pyrimidinesulfamide aprocitentan Download PDF

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Publication number
WO2018154101A1
WO2018154101A1 PCT/EP2018/054627 EP2018054627W WO2018154101A1 WO 2018154101 A1 WO2018154101 A1 WO 2018154101A1 EP 2018054627 W EP2018054627 W EP 2018054627W WO 2018154101 A1 WO2018154101 A1 WO 2018154101A1
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WIPO (PCT)
Prior art keywords
pyrimidin
bromo
compound
crystalline form
ray powder
Prior art date
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PCT/EP2018/054627
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English (en)
Inventor
Martin Bolli
Philipp KOHLER
Ivan SCHINDELHOLZ
Markus Von Raumer
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Idorsia Pharmaceuticals Ltd
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Publication date
Priority to CN201880014146.8A priority Critical patent/CN110381948A/zh
Priority to BR112019017644-6A priority patent/BR112019017644A2/pt
Priority to AU2018225309A priority patent/AU2018225309B2/en
Priority to KR1020197028200A priority patent/KR102577375B1/ko
Priority to EA201991978A priority patent/EA201991978A1/ru
Priority to CN202311718027.XA priority patent/CN117946011A/zh
Priority to JP2019546286A priority patent/JP2020508338A/ja
Priority to EP21202979.7A priority patent/EP4014976B1/fr
Priority to EP18708945.3A priority patent/EP3585391A1/fr
Priority to MX2019010221A priority patent/MX2019010221A/es
Priority to US16/489,194 priority patent/US10919881B2/en
Priority to SG11201907604UA priority patent/SG11201907604UA/en
Application filed by Idorsia Pharmaceuticals Ltd filed Critical Idorsia Pharmaceuticals Ltd
Priority to IL297993A priority patent/IL297993B1/en
Priority to CA3053994A priority patent/CA3053994A1/fr
Publication of WO2018154101A1 publication Critical patent/WO2018154101A1/fr
Priority to PH12019501937A priority patent/PH12019501937A1/en
Priority to IL26885219A priority patent/IL268852A/en
Priority to US17/146,801 priority patent/US11680058B2/en
Priority to JP2022201112A priority patent/JP7520951B2/ja
Priority to US18/319,402 priority patent/US20230391757A1/en

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    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
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    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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Definitions

  • the present invention concerns novel crystalline forms of (5-(4-bromo-phenyl)- 6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl ⁇ -sulfamide (hereinafter also referred to as "COMPOUND”), processes for the preparation thereof, pharmaceutical compositions comprising said crystalline forms, pharmaceutical compositions prepared from such crystalline forms, and their use as endothelin receptor inhibitors and endothelin receptor antagonists. It also relates to uses of the COMPOUND for treating particular diseases or disorders, either alone or in combination with other active ingredients or therepautic agents.
  • COMPOUND novel crystalline forms of (5-(4-bromo-phenyl)- 6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl ⁇ -sulfamide
  • Aprocitentan also known under the name ACT- 132577, is an endothelin receptor inhibitor and useful as endothelin receptor antagonist.
  • the compound of formula I is a member of a structural family that was previously generically disclosed in WO 02/053557.
  • the compound of formula I while showing endothelin receptor antagonist activity, exhibits in vivo a much longer half-life and a much shorter clearance in comparison to corresponding alkylated derivatives. This makes the compound of formula I particularly suitable for long-acting pharmaceutical compositions, as disclosed in WO 2009/024906.
  • Certain manufacturing processes relating to aprocitentan are disclosed in WO2015/121397.
  • COMPOUND can be used for treatment of endothelin related diseases which are associated with an increase in vasoconstriction, proliferation or inflammation due to endothelin.
  • endothelin related diseases are hypertension, pulmonary hypertension, coronary diseases, cardiac insufficiency, renal and myocardial ischemia, renal failure, cerebral ischemia, dementia, migraine, subarachnoidal hemorrhage, Raynaud's syndrome, digital ulcers and portal hypertension.
  • CKD chronic kidney disease
  • diabetes diabetic nephropathy, diabetic retinopathy, diabetic vasculopathy, chronic heart failure and diastolic dysfunction
  • they can further be used in the treatment or prevention of atherosclerosis, restenosis after balloon or stent angioplasty, inflammation, stomach and duodenal ulcer, cancer, melanoma, prostate cancer, prostatic hypertrophy, erectile dysfunction, hearing loss, amaurosis, chronic bronchitis, asthma, pulmonary fibrosis, gram negative septicemia, shock, sickle cell anemia, glomerulonephritis, renal colic, glaucoma, connective tissue diseases, therapy and prophylaxis of diabetic complications, complications of vascular or cardiac surgery or after organ transplantation, complications of cyclosporin treatment, pain, hyperlipidemia as well as other diseases, presently known to be related to endothelin.
  • CKD chronic kidney disease
  • atherosclerosis restenosis after balloon or stent angi
  • resistant hypertension (or difficult to treat hypertension) is defined as uncontrolled blood pressure (BP) (i.e., failure to lower BP to a pre-defined threshold) despite concurrent administration of three antihypertensive therapies of different pharmacological classes at maximal or optimal doses, including a diuretic.
  • BP blood pressure
  • resistant hypertension patients include patients whose blood pressure is controlled with use of more than three medications. That is, patients whose blood pressure is controlled but require four or more medications to do so should be considered resistant to treatment (see e.g. Mancia et al, J. Hypertens. (2013)).
  • ERAs endothelin receptor antagonists
  • therapeutic benefit needs to be weighted against potential side effects, such as the potential risk of teratogenic activity.
  • selective ETA-antagonists and dual antagonists of both the ETA and ETB receptor may cause cause fluid retention, a common side effect associated with many previously studied ERAs and sometimes (e.g. if not manageable with diuretics) leading to exaggerated major adverse cardiac events such as heart failure or death.
  • the risk-benefit balance is in most cases in favor of treatment with an ERA for indications such as pulmonary hypertension (as reflected in the past by successive market approvals e.g.
  • ERAs have no role in the management of primary hypertension (Laffin et al. Seminars in Nephrology 2015, 35, 168- 175), and side effects such as fluid retention may remain an issue when a potential treatment of rHT, chronic kidney disease or other hypertension related diseses with an ERA is considered.
  • the ETA-selective endothelin receptor antagonist darusentan has been in development for the treatment of rHT (Bakris et al, Hypertension 2010, 56,824-830, see also WO2007/098390).
  • rHT The ETA-selective endothelin receptor antagonist darusentan
  • rHT Hypertension 2010, 56,824-830, see also WO2007/098390.
  • systolic blood pressure failed to show significant treatment effect on the primary endpoint systolic blood pressure.
  • Patients were eligible to participate if they had treatment resistant hypertension (systolic blood pressure of higher than 140 mm Hg) despite treatment with three or more antihypertensive drugs from different drug classes, including a diuretic, at optimized doses.
  • WO2016/073846 concludes in proposing a method of treating CKD with an ERA, especially with the ETA-selective ERA atrasentan, using predictors of fluid retention; said method comprising the determination of a risk of fluid retention if an ERA were administered to the subject; and administering the ERA to the subject if the risk is at an acceptable level.
  • aprocitentan an ERA resulting in effective dual blockade of the endothelin receptors, may result in efficacious control of blood pressure in subjects having essential hypertension.
  • aprocitentan was administered as monotherapy, i.e. without background anti-hypertensive therapy) (Actelion Pharmaceuticals Ltd, press release May 22, 2017).
  • Actelion Pharmaceuticals Ltd press release May 22, 2017.
  • some indications of potential fluid retention were observed (e.g. increased body weight at higher doses, dose related decrease in the hemoglobin concentration, four cases of peripheral edema at higher doses), the overall frequency of adverse events was similar to those observed in the placebo group.
  • aprocitentan when used in the treatment of hypertension related diseases, especially resistant hypertension.
  • aprocitentan may have a different pharmacological profile than the predominantly ETA- selective antagonists so far tested in resistant hypertension or chronic kidney disease in diabetic and non-diabetic patients.
  • certain crystalline forms of COMPOUND may under certain conditions be found. Said crystalline forms of COMPOUND are novel and may have advantageous properties in view of the potential use of COMPOUND as active pharmaceutical ingredient.
  • Such advantages may include better flow properties; less hygroscopicity; better reproducibiliy in manufacturing (for example better filtration parameters, better reproducibility of formation, and/or better sedimentation); and/or defined morphology.
  • Such crystalline forms of COMPOUND may be particularly suitable in a process of manufacturing certain pharmaceutical compositions. It has also been found that COMPOUND or a pharmaceutically acceptable salt thereof is particularly useful to treat certain disorders, in particular when used in combination with other active ingredients or therepeutic agents
  • Figure 1 shows the X-ray powder diffraction diagram of COMPOUND in a crystalline form A, e.g. as obtained from Example 1.
  • the X-ray diffraction diagram shows peaks having a relative intensity, as compared to the most intense peak in the diagram, of the following percentages (relative peak intensitites given in parenthesis) at the indicated angles of refraction 2theta (selected peaks from the range 3-33° 2theta with relative intensity larger then 10% are reported): 9.8° (18%), 9.9° (18%), 1 1.7° (14%), 14.5° (10%), 15.4° (14%), 15.6° (29%), 16.9° (19%), 17.2° (16%), 17.8° (100%), 18.6° (50%), 19.9° (54%), 20.0° (67%), 21.5° (24%), 21.9° (10%), 22.8° (18%), 23.2° (49%), 23.5° (83%), 24.9° (32%), 25.1° (20%), 25.3° (24%), 25.6° (33%), 25.
  • Figure 2 shows the X-ray powder diffraction diagram of a dichloromethane solvate of the COMPOUND in a crystalline form B, e.g. as obtained from Example 2.
  • the X-ray diffraction diagram shows peaks having a relative intensity, as compared to the most intense peak in the diagram, of the following percentages (relative peak intensitites given in parenthesis) at the indicated angles of refraction 2theta (selected peaks from the range 3- 33° 2theta with relative intensity larger then 10% are reported): 1 1.2° (16%), 16.2° (57%), 18.0° (21%), 18.6° (71%), 18.8° (36%), 19.8° (19%), 20.3° (100%), 22.4° (45%), 22.9° (28%), 24.3° (44%), 24.8° (1 1%), 25.0° (41%), 25.7° (22%), 26.1° (31%), 27.4° (20%), 29.4° (16%), 29.8° (38%) and 32.4° (12%).
  • Figure 3 shows the X-ray powder diffraction diagram of COMPOUND in a crystalline form C, e.g. as obtained from Example 3.
  • the X-ray diffraction diagram shows peaks having a relative intensity, as compared to the most intense peak in the diagram, of the following percentages (relative peak intensitites given in parenthesis) at the indicated angles of refraction 2theta (selected peaks from the range 3-33° 2theta with relative intensity larger then 10% are reported): 7.8° (23%), 9.7° (42%), 15.7° (37%), 17.2° (16%), 17.8° (15%), 18.8° (26%), 19.8° (71%), 20.1° (51%), 20.6° (15%), 21.6° (15%), 22.0° (100%), 23.4° (27%), 23.6° (40%), 24.1° (23%), 24.5° (16%), 25.1° (13%), 25.3° (39%), 25.7° (28%), 26.8° (19%), 27.1° (16%), 28.5° (31%), 30.8
  • Figure 4 shows the X-ray powder diffraction diagram of COMPOUND in a crystalline form D, e.g. as obtained from Example 4.
  • the X-ray diffraction diagram shows peaks having a relative intensity, as compared to the most intense peak in the diagram, of the following percentages (relative peak intensitites given in parenthesis) at the indicated angles of refraction 2theta (selected peaks from the range 3-33° 2theta with relative intensity larger then 10% are reported): 4.6° (27%), 8.4° (15%), 8.6° (11%), 16.4° (17%), 16.8° (26%), 17.2° (10%), 18.6° (11%), 18.9° (18%), 19.3° (40%), 19.6° (45%), 20.1° (100%), 20.6° (55%), 20.8° (26%), 22.0° (10%), 22.7° (14%), 23.0° (24%), 23.5° (32%), 23.8° (12%), 24.2° (17%), 24.7° (20%), 25.1° (55%), 25.4
  • Figure 5 shows the X-ray powder diffraction diagram of an acetonitrile solvate of the COMPOUND in a crystalline form E, e.g. as obtained from Example 5.
  • the X-ray diffraction diagram shows peaks having a relative intensity, as compared to the most intense peak in the diagram, of the following percentages (relative peak intensitites given in parenthesis) at the indicated angles of refraction 2theta (selected peaks from the range 3- 33° 2theta with relative intensity larger then 10% are reported): 9.0° (21%), 9.5° (56%), 11.3° (61%), 14.5° (41%), 14.8° (15%), 15.6° (47%), 16.0° (26%), 16.5° (100%), 18.2° (84%), 18.7° (73%), 18.9° (56%), 20.2° (20%), 20.7° (56%), 22.8° (96%), 23.9° (22%), 24.5° (70%), 25.3° (77%), 25.6° (29%), 26.0° (14%), 26.6°
  • Figure 6 shows the X-ray powder diffraction diagram of COMPOUND in a crystalline form J, e.g. as obtained from Example 6.
  • the X-ray diffraction diagram shows peaks having a relative intensity, as compared to the most intense peak in the diagram, of the following percentages (relative peak intensitites given in parenthesis) at the indicated angles of refraction 2theta (selected peaks from the range 3-33° 2theta with relative intensity larger then 10% are reported): 4.0° (44%), 4.7° (14%), 6.5° (23%), 9.0° (27%), 16.1° (40%), 17.2° (1 1%), 18.7° (22%), 19.0° (58%), 19.4° (28%), 19.8° (46%), 20.7° (57%), 21.2° (17%), 21.9° (100%), 22.6° (14%), 23.2° (23%), 24.1° (37%), 24.8° (40%), 25.6° (42%), 27.0° (29%), 28.2° (27%), 29.0° (20%),
  • Figure 7 shows the X-ray powder diffraction diagram of a dimethylsulfoxide solvate of the COMPOUND in a crystalline form K, e.g. as obtained from Example 7.
  • the X-ray diffraction diagram shows peaks having a relative intensity, as compared to the most intense peak in the diagram, of the following percentages (relative peak intensitites given in parenthesis) at the indicated angles of refraction 2theta (selected peaks from the range 3- 33° 2theta with relative intensity larger then 10% are reported): 10.9° (16%), 16.9° (18%), 18.2° (26%), 18.4° (30%), 18.6° (29%), 18.7° (55%), 19.3° (100%), 20.8° (35%), 21.2° (47%), 21.9° (26%), 24.3° (21%), 24.8° (24%), 25.4° (29%), 25.8° (22%), 26.7° (34%), 27.7° (13%), 27.8° (14%), 28.6° (15%), 29.4°
  • Figure 8 shows the X-ray powder diffraction diagram of an ethanol solvate of the COMPOUND in a crystalline form L, e.g. as obtained from Example 8.
  • the X-ray diffraction diagram shows peaks having a relative intensity, as compared to the most intense peak in the diagram, of the following percentages (relative peak intensitites given in parenthesis) at the indicated angles of refraction 2theta (selected peaks from the range 3- 33° 2theta with relative intensity larger then 10% are reported): 9.1° (31%), 9.3° (34%), 11.3° (49%), 12.2° (10%), 14.6° (17%), 14.8° (46%), 15.7° (16%), 16.1° (10%), 16.4° (80%), 17.9° (17%), 18.2° (19%), 18.7° (96%), 20.0° (38%), 20.3° (100%), 22.6° (1 1%), 22.8° (76%), 23.2° (50%), 24.1° (14%), 24.5° (56%), 24.7° (68%),
  • Figure 9 shows the acute effects of COMPOUND on mean arterial blood pressure ("MAP") in conscious, male hypertensive Dahl salt sensitive rats.
  • Figure 10 shows the acute effects of COMPOUND on MAP in conscious, male hypertensive deoxycorticosterone acetate salt rats.
  • Figure 11 shows the acute effects of COMPOUND on MAP in conscious, male spontaneaously hypertensive rats.
  • Figure 12 shows the acute effects of COMPOUND, used alone or in combination with valsartan, on MAP in conscious, male spontaneaously hypertensive rats.
  • Figure 13 shows the acute effects of COMPOUND, used alone or in combination with valsartan, on MAP in conscious, male hypertensive deoxycorticosterone acetate salt rats.
  • Figure 14 shows the acute effects of COMPOUND, used alone or in combination with enalapril, on MAP in conscious, male spontaneaously hypertensive rats.
  • Figure 15 shows the acute effects of COMPOUND, used alone or in combination with amlodipine, on MAP in conscious, male hypertensive deoxycorticosterone acetate salt rats.
  • Figure 16 shows the effects of chronic oral administration of COMPOUND on MAP in conscious, male hypertensive deoxycorticosterone acetate salt rats.
  • Figure 17 shows the effects of chronic oral administration of COMPOUND on renal vascular resistance in conscious, male hypertensive deoxycorticosterone acetate salt rats.
  • Figure 18 shows the effects of a single dose oral administration of COMPOUND on haematocrit (Hct) male Wistar rats.
  • Figure 19 shows the gravimetric vapour sorption diagram of COMPOUND in a crystalline form A as obtained from Example 1.
  • Figure 20 shows the gravimetric vapour sorption diagram of COMPOUND in a crystalline form C as obtained from Example 3.
  • a first embodiment of the invention relates to crystalline forms of the COMPOUND ⁇ 5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl ⁇ - sulfamide or of a solvate of that compound, characterized by:
  • said X-ray powder diffraction diagram is obtained by using combined Cu K l and Kcc2 radiation, without Kcc2 stripping; and the accuracy of the 2 ⁇ values is in the range of 2 ⁇ +/- 0.2°.
  • the crystalline forms according to embodiment 1) comprise the COMPOUND in a crystalline form of the free base (i.e. not in form of a salt).
  • said crystalline forms may comprise non-coordinated and / or coordinated solvent. Coordinated solvent is used herein as term for a crystalline solvate.
  • non- coordinated solvent is used herein as term for physiosorbed or physically entrapped solvent (definitions according to Polymorphism in the Pharmaceutical Industry (Ed. R. Hilfiker, VCH, 2006), Chapter 8: U.J. Griesser: The Importance of Solvates).
  • Crystalline forms A and C are anhydrate or ansolvate forms i.e.
  • crystalline form B is a DCM solvate
  • crystalline form E is a MeCN solvate
  • crystalline form K is a DMSO solvate
  • crystalline form L is an ethanol solvate.
  • Another embodiment relates to a crystalline form of the COMPOUND or of a solvate of that compound, characterized by:
  • ⁇ form D of the COMPOUND comprising the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2 ⁇ : 4.6°, 16.4°, 16.8°, 19.3°, 19.6°, 20.1°, 20.6°, 23.0°, 23.5°, and 25.1°; or
  • Another embodiment relates to a crystalline form of the COMPOUND or of a solvate thereof, characterized by:
  • Another embodiment relates to a crystalline form of the COMPOUND or of a solvate thereof; characterized by:
  • the present data show peaks having a relative intensity, as compared to the most intense peak in the diagram, of the following percentages (relative peak intensitites given in parentheses) at the indicated angles of refraction 2theta (selected peaks from the range 3-33° 2theta with relative intensity larger then 10% are reported).
  • Another embodiment relates to a crystalline form of the COMPOUND or of a solvate thereof which essentially shows the X-ray powder diffraction pattern as depicted in any one of the Figures 1, 3, 4, 5, 6, 7 and 8, wherein said X-ray powder diffraction diagram is obtained by using combined Cu Keel and Kcc2 radiation, without Kcc2 stripping; and the accuracy of the 2 ⁇ values is in the range of 2 ⁇ +/- 0.2°.
  • the term "essentially” means that at least the major peaks of the diagram depicted in said figures, i.e. those having a relative intensity of more than 10%, especially more than 20%, as compared to the most intense peak in the diagram, have to be present.
  • the person skilled in the art of X-ray powder diffraction will recognize that relative intensities in X-ray powder diffraction diagrams may be subject to strong intensity variations due to preferred orientation effects.
  • a particular sub-embodiment of embodiment 6) relates to a crystalline form of COMPOUND which essentially shows the X-ray powder diffraction pattern as depicted in
  • the present invention relates to a crystalline form of the COMPOUND or of a solvate thereof wherein
  • form D is obtainable by crystallisation of form A from methyl-ethylketone
  • form J is obtainable by crystallisation of form B from DMSO and water;
  • (k) form K is obtainable by crystallisation of the COMPOUND in an aqueous solution; (1) form L is obtainable by crystallisation of form K from EtOH. 9)
  • Another embodiment of the present invention relates to a crystalline form A of the COMPOUND comprising the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2 ⁇ : 17.8°, 20.0°, and 23.5°; whereby it is an anhydrate or ansolvate form.
  • the X-ray powder diffraction diagram may further comprise the peaks as disclosed in embodiment 2), 3), 4), 5) or 6).
  • said crystalline form may be further characterized by an endothermic event with a peak of the endotherm observed at about 159°C as determined by DSC, e.g. using the method disclosed in the experimental part.
  • Another embodiment of the present invention relates to a crystalline form A of the COMPOUND comprising the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2 ⁇ : 17.8°, 20.0°, and 23.5°; whereby it is an anhydrate or ansolvate form which is obtainable by crystallisation in an aqueous solution at pH 6.2 to 6.8. It is understood that the X-ray powder diffraction diagram may further comprise the peaks as disclosed in embodiment 2), 3), 4), 5) or 6).
  • Another embodiment of the present invention relates to a crystalline form B of a dichloromethane solvate of the COMPOUND comprising the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2 ⁇ : 16.2°, 18.6°, and 20.3° (notably 16.2°, 18.6°, 20.3°, 22.4° and 24.3°, especially 9.0°, 11.2°, 16.2°, 18.0°, 18.6°, 19.8°, 20.3°, 22.4°, 22.9° and 24.3°).
  • Another embodiment of the present invention relates to a crystalline form B of a dichloromethane solvate of the COMPOUND comprising the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2 ⁇ : 16.2°, 18.6°, and 20.3° (notably 16.2°, 18.6°, 20.3°, 22.4° and 24.3°, especially 9.0°, 11.2°, 16.2°, 18.0°, 18.6°, 19.8°, 20.3°, 22.4°, 22.9° and 24.3°); whereby this form is obtainable by crystallisation from dichloromethane at pH 7.
  • Another embodiment of the present invention relates to a crystalline form C of the COMPOUND comprising the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2 ⁇ : 9.7°, 15.7°, and 22.0°; whereby it is an anhydrate or ansolvate form.
  • the X-ray powder diffraction diagram may further comprise the peaks as disclosed in embodiment 2), 3), 4), 5) or 6).
  • said crystalline form may be further characterized by an endothermic event with a peak of the endotherm observed at about 153°C as determined by DSC, e.g. using the method disclosed in the experimental part.
  • Another embodiment of the present invention relates to a crystalline form C of the COMPOUND comprising the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2 ⁇ : 9.7°, 15.7°, and 22.0°; whereby it is an anhydrate or ansolvate form which is obtainable by crystallisation MeOH, EtOH or propan-2-ol. It is understood that the X-ray powder diffraction diagram may further comprise the peaks as disclosed in embodiment 2), 3), 4), 5) or 6).
  • Another embodiment of the present invention relates to a crystalline form D of the COMPOUND comprising the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2 ⁇ : 4.6°, 16.8°, and 20.1°; whereby it is obtainable by crystallisation of form A from methyl-ethylketone. It is understood that the X-ray powder diffraction diagram may further comprise the peaks as disclosed in embodiment 2), 3), 4), 5) or 6).
  • Another embodiment of the present invention relates to a crystalline form E of an acetonitrile solvate of the COMPOUND comprising the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2 ⁇ : 9.5°, 16.5°, and 18.2°. It is understood that the X-ray powder diffraction diagram may further comprise the peaks as disclosed in embodiment 2), 3), 4), 5) or 6).
  • Another embodiment of the present invention relates to a crystalline form E of an acetonitrile solvate of the COMPOUND comprising the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2 ⁇ : 9.5°, 16.5°, and 18.2°; whereby this form is obtainable by crystallisation of form A from acetonitrile.
  • the X-ray powder diffraction diagram may further comprise the peaks as disclosed in embodiment 2), 3), 4), 5) or 6).
  • Another embodiment of the present invention relates to a crystalline form J of the COMPOUND comprising the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2 ⁇ : 4.0°, 16.1°, and 21.9°; whereby it is obtainable by crystallisation of form B of a dichloromethane solvate of the COMPOUND from DMSO and water.
  • the X-ray powder diffraction diagram may further comprise the peaks as disclosed in embodiment 2), 3), 4), 5) or 6).
  • Another embodiment of the present invention relates to a crystalline form K of a dimethylsulfoxide solvate of the COMPOUND comprising the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2 ⁇ : 16.9°, 19.3°, and 24.8°. It is understood that the X-ray powder diffraction diagram may further comprise the peaks as disclosed in embodiment 2), 3), 4), 5) or 6).
  • Another embodiment of the present invention relates to a crystalline form K of a dimethylsulfoxide solvate of the COMPOUND comprising the presence of peaks in the X- ray powder diffraction diagram at the following angles of refraction 2 ⁇ : 16.9°, 19.3°, and 24.8°; whereby this form is obtainable by crystallisation in an aqueous solution.
  • the X-ray powder diffraction diagram may further comprise the peaks as disclosed in embodiment 2), 3), 4), 5) or 6).
  • Another embodiment of the present invention relates to a crystalline form L of an ethanol solvate of the COMPOUND comprising the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2 ⁇ : 1 1.3°, 16.4°, and 20.3°; whereby it is obtainable by crystallisation of form K from ethanol.
  • the X-ray powder diffraction diagram may further comprise the peaks as disclosed in embodiment 2), 3), 4), 5) or 6).
  • the 2 ⁇ value given is to be understood as an interval from said value minus 0.2° to said value plus 0.2° (2 ⁇ +/- 0.2°); and preferably from said value minus 0.1° to said value plus 0.1° (2 ⁇ +/- 0.1 0 ).
  • n equivalent(s) is used wherein n is a number, it is meant and within the scope of the current application that n is referring to about the number n, preferably n is referring to the exact number n.
  • Another embodiment of the present invention relates to an amorphous form of the COMPOUND ⁇ 5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin- 4-yl ⁇ -sulfamide.
  • the amorphous form may be obtained by milling form A.
  • the amorphous form is obtainable by milling in a ball mill (MM200 Retsch Ball Mill, 2 agate beads), 30 min at 30 Hz at ambient temperature.
  • the crystalline forms, especially the essentially pure crystalline forms, of the COMPOUND according to any one of embodiments 1) to 21) can be used as medicaments, e.g. in the form of pharmaceutical compositions for enteral or parenteral administration.
  • the crystalline solid, especially the essentially pure crystalline solid, of COMPOUND according to any one of embodiments 1) to 21) may be used as single component or as mixtures with other crystalline forms or the amorphous form of COMPOUND.
  • compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5, "Pharmaceutical Manufacturing” [published by Lippincott Williams & Wilkins]) by bringing the crystalline forms of the present invention, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, pharmaceutically acceptable solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
  • Another embodiment of the present invention relates to a crystalline form of the COMPOUND or of a solvate of that compound, according to any one of embodiments 1) to 21), for the use in the manufacture of a pharmaceutical composition, wherein said pharmaceutical composition comprises as active ingredient the compound ⁇ 5-(4-bromo- phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl ⁇ -sulfamide, and at least one therapeutically inert excipient.
  • compositions according to embodiment 25) are especially useful for the treatment of hypertension, pulmonary hypertension, coronary diseases, cardiac insufficiency, renal and myocardial ischemia, renal failure, cerebral ischemia, dementia, migraine, subarachnoidal hemorrhage, Raynaud's syndrome, digital ulcers or portal hypertension as well as for the treatment or prevention of atherosclerosis, restenosis after balloon or stent angioplasty, inflammation, stomach and duodenal ulcer, cancer, melanoma, prostate cancer, prostatic hypertrophy, erectile dysfunction, hearing loss, amaurosis, chronic bronchitis, asthma, pulmonary fibrosis, gram negative septicemia, shock, sickle cell anemia, glomerulonephritis, renal colic, glaucoma, connective tissue diseases, diabetic complications, complications of vascular or cardiac surgery or after organ transplantation, complications of cyclosporin treatment, pain or hyperlipidemia.
  • compositions according to embodiment 25 are also useful for the treatment of Chronic Kidney Disease (CKD), especially CKD of stages 1 to 4 as defined by the Kidney Disease Improving Global Outcomes (KDIGO) Guidelines (and notably CKD of stage 3), and in particular CKD (notably of these stages) caused by essential hypertension.
  • CKD Chronic Kidney Disease
  • KDIGO Kidney Disease Improving Global Outcomes
  • CKD CKD of stage 3
  • CKD notably of these stages
  • a disease selected from the group consisting of hypertension, pulmonary hypertension, diabetic arteriopathy, heart failure, erectile dysfunction, angina pectoris and CKD [especially CKD of stages 1 to 4 as defined by the Kidney Disease Improving Global Outcomes (KDIGO) Guidelines (and notably CKD of stage 3); and in particular CKD (notably of these stages) caused by essential hypertension].
  • KDIGO Kidney Disease Improving Global Outcomes
  • CKD notably of these stages
  • a disease selected from the group consisting of essential hypertension, resistant hypertension, pulmonary hypertension and pulmonary arterial hypertension (and notably in the treatment of resistant hypertension).
  • Essential hypertension also called primary hypertension or idiopathic hypertension
  • TSBP systolic blood pressure
  • Individuals with high normal blood pressure tend to maintain pressures that are above average for the general population and are at greater risk for development of definite hypertension and cardiovascular events than the general population.
  • the threshold value TSBP above which treatment is recommended is regularly discussed among clinicians (see e.g. Mancia et al, J. Hypertens. (2013), 31, 1281-1357); accordingly, depending on the patient's general condition and age, TSBP could be 140 or 130 mm Hg, or another suitable value.
  • resistant hypertension in the present invention is defined as blood pressure that remains above goal in spite of the concurrent use of 3 antihypertensive agents of different classes.
  • One of the 3 agents should be a diuretic and all agents should be prescribed at optimal/maximal dose amounts.
  • resistant hypertension patients include patients whose blood pressure is controlled with use of more than 3 medications. That is, patients whose blood pressure is controlled but require 4 or more medications to do so should be considered resistant to treatment (see e.g. Mancia et al, J. Hypertens. (2013), 31, 1281-1357).
  • Diuretic in particular means in the present application a diuretic of the thiazide class (a thiazide-like diuretic) such as especially chlorthalidone, hydrochlorothiazide, chlorothiazide, indapamide, or metolazone.
  • Preferred diuretics are chlorthalidone or hydrochlorothiazide.
  • the invention thus, further relates to COMPOUND, especially a crystalline form of COMPOUND according to any one of embodiments 1) to 21) (in particular crystalline Form A or C), wherein COMPOUND / said crystalline form is used as a medicament, especially for the treatment of resistant hypertension; wherein COMPOUND / said crystalline form is used alone or (preferably) in combination (preferably for simultaneously adminiatration, including a fixed dose combination) with a diuretic, in particular hydrochlorothiazide (HCTZ or HCT).
  • HCTZ hydrochlorothiazide
  • said combination of COMPOUND / said crystalline form according to any one of embodiments 1) to 21) (in particular crystalline Form A or C) with a diuretic, in particular hydrochlorothiazide (HCTZ or HCT) for the treatment of resistant hypertension; may require further combination (preferably for simultaneously adminiatration, including a fixed dose combination) with one or two additional active ingredients that are antihypertensive agents of different classes (especially a CCB and/or an ARB), in particular valsartan.
  • HCTZ or HCT hydrochlorothiazide
  • the invention thus, especially relates to pharmaceutical compositions comprising COMPOUND / the respective crystalline form of COMPOUND as defined in any one of embodiments 26) to 31) below; comprising as active ingredients, in addition to COMPOUND / the respective crystalline form of COMPOUND, a diuretic, in particular hydrochlorothiazide (HCTZ or HCT); and optionally further comprising one or two active ingredients that are antihypertensive agents of different classes (especially a CCB and/or an ARB); in particular further comprising valsartan.
  • HCTZ hydrochlorothiazide
  • Another embodiment of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising as active ingredient a crystalline form of the COMPOUND according to any one of embodiments 1) to 21), and at least one therapeutically inert excipient.
  • the invention thus also relates to a solid pharmaceutical composition (in particular in the form of a tablet) comprising COMPOUND, especially a crystalline form of the COMPOUND according to any one of embodiments 1) to 21) (especially solid form A of the COMPOUND, as described in any one of embodiments 1) to 7)), microcrystalline cellulose, lactose, hydroxypropylcellulose, croscarmellose sodium and magnesium stearate; it will in particular relate to a solid pharmaceutical composition (in particular in the form of a tablet) consisting of a crystalline form of the COMPOUND according to any one of embodiments 1) to 21) (especially solid form A thereof, as described in any one of embodiments 1) to 7)), microcrystalline cellulose, lactose, hydroxypropylcellulose, croscarmellose sodium and magnesium stearate.
  • a solid pharmaceutical composition in particular in the form of a tablet
  • a solid pharmaceutical composition consisting of a crystalline form of the COMPOUND according to any one of embodiments 1) to 21) (especially solid form
  • the solid pharmaceutical composition of embodiment 27) will comprise COMPOUND, especially the crystalline form of the COMPOUND according to any one of embodiments 1) to 21) (especially solid form A of the COMPOUND, as described in any one of embodiments 1) to 7)) in a total amount from 1 to 25% (especially 5 to 25%) in weight based on the total weight of the pharmaceutical composition, microcrystalline cellulose in a total amount from 20 to 35 % (especially 20 to 30%) in weight based on the total weight of the pharmaceutical composition, lactose in a total amount from 40 to 65% in weight based on the total weight of the pharmaceutical composition, hydroxypropylcellulose in a total amount from 1 to 3% in weight based on the total weight of the pharmaceutical composition, croscarmellose sodium in a total amount from 2 to 8% in weight based on the total weight of the pharmaceutical composition and magnesium stearate in a total amount from 0.2 to 2% in weight based on the total weight of the pharmaceutical composition, whereby the total percent in weight of the solid pharmaceutical composition will be COMPOUND,
  • compositions according to any of embodiments 26) to 28) are especially useful for the treatment of endothelin related diseases and disorders, notably the diseases and disorders of embodiment 25).
  • a further embodiment of the invention relates to a pharmaceutical composition according to any one of embodiments 26) to 28), wherein said pharmaceutical composition is in form of a tablet.
  • the pharmaceutical composition of embodiment 29) will be in the form of a tablet consisting of the solid form A of the COMPOUND (as described in any one of embodiments 1) to 7)) in a total amount from 1 to 25% (especially 5 to 25%) in weight based on the total weight of the pharmaceutical composition, microcrystalline cellulose in a total amount from 20 to 35 % (especially 20 to 30%) in weight based on the total weight of the pharmaceutical composition, lactose in a total amount from 40 to 65% in weight based on the total weight of the pharmaceutical composition, hydroxypropylcellulose in a total amount from 1 to 3% in weight based on the total weight of the pharmaceutical composition, croscarmellose sodium in a total amount from 2 to 8% in weight based on the total weight of the pharmaceutical composition and magnesium stearate in a total amount from 0.2 to 2% in weight based on the total weight of the pharmaceutical composition, whereby the total percent in weight of the solid pharmaceutical composition will always be 100.
  • a tablet according to embodiment 29) or 30) can optionally be coated with a suitable protective pellicle.
  • Said protective pellicle will notably prevent direct contact of the pharmaceutical composition with moisture; it may also ease imprints that may be desired to be used in order to distinguish the pharmaceutical composition from others.
  • the coating material for making such protective pellicle may include a low water vapour permeability polymer (such as a polyvinyl alcohol (e.g. Aquapolish ® white PVA from manufacturer Biogrund) or dimethylaminoethyl methacrylate (e.g. EUDRAGIT ® E PO)).
  • the coating material can further include a plasticizing agent (e.g. propylene glycol, triacetyne, dibutyl phthalate or dibutyl sebacate), a surfactant (e.g. sodium lauryl sulphate or a polysorbate such as Tween ® ) and/or a lubricant/glidant (e.g. stearic acid, magnesium or calcium stearate or talc).
  • the coating material can also include a pigment (e.g. iron(II) oxide, iron(III) oxide or titanium oxide) to give the tablet a coloured aspect.
  • a further embodiment of the invention relates to a pharmaceutical composition according to any one of embodiments 26) to 28), wherein said pharmaceutical composition is in form of a capsule.
  • embodiments 25), 26), 27), 28), 29), 30) or 31) especially refer to the crystalline forms according to any one of embodiments 1) to 21) which is suitable / which is used as final isolation step of COMPOUND (e.g. in order to meet the purity requirements of pharmaceutical production), whereas the final pharmaceutical composition according to embodiment 25), 26), 27), 28) , 29), 30) or 31) may or may not contain said crystalline form (e.g. because the originally crystalline form of COMPOUND is further transformed during the manufacturing process and / or is dissolved in the pharmaceutically acceptable carrier material(s); thus, in the final pharmaceutical composition, COMPOUND may be present in non-crystalline form, in another crystalline form, or in dissolved form, or the like).
  • a further embodiment of the invention relates to COMPOUND or a pharmaceutically acceptable salt thereof, especially a crystalline form of COMPOUND according to any one of embodiments 1) to 21), for use in the treatment of hypertension, pulmonary hypertension, coronary diseases, cardiac insufficiency, renal and myocardial ischemia, renal failure, cerebral ischemia, dementia, migraine, subarachnoidal hemorrhage, Raynaud's syndrome, digital ulcers or portal hypertension as well as for the treatment or prevention of atherosclerosis, restenosis after balloon or stent angioplasty, inflammation, stomach and duodenal ulcer, cancer, melanoma, prostate cancer, prostatic hypertrophy, erectile dysfunction, hearing loss, amaurosis, chronic bronchitis, asthma, pulmonary fibrosis, gram negative septicemia, shock, sickle cell anemia, glomerulonephritis, renal colic, glaucoma, connective tissue diseases, diabetic complications, complications of vascular or cardiac surgery or after
  • a further embodiment of the invention relates to COMPOUND or a pharmaceutically acceptable salt thereof, especially a crystalline form of COMPOUND according to any one of embodiments 1) to 21), for use in the treatment of a disease selected from the group consisting of hypertension, pulmonary hypertension, diabetic arteriopathy, heart failure, erectile dysfunction, angina pectoris and CKD [especially CKD of stages 1 to 4 as defined by the Kidney Disease Improving Global Outcomes (KDIGO) Guidelines (and notably CKD of stage 3), and in particular CKD (notably of these stages) caused by essential hypertension].
  • KDIGO Kidney Disease Improving Global Outcomes
  • a further embodiment of the invention relates to COMPOUND or a pharmaceutically acceptable salt thereof, especially a crystalline form of COMPOUND according to any one of embodiments 1) to 21), for use in the treatment of a disease selected from the group consisting of essential hypertension, resistant hypertension, pulmonary hypertension and pulmonary arterial hypertension (and notably for use in the treatment of resistant hypertension).
  • COMPOUND crystalline form of COMPOUND
  • such compounds are likewise suitable for use in the preparation of a medicament for the prevention / prophylaxis or treatment of said diseases.
  • such compounds are also suitable in a method for the prevention / prophylaxis or treatment of such diseases, comprising administering to a subject (mammal, especially human) in need thereof, an effective amount of such compound.
  • a further embodiment of the invention relates to the use of COMPOUND or a pharmaceutically acceptable salt thereof, especially of a crystalline form of COMPOUND according to any one of embodiments 1) to 21), for the preparation of a medicament intended for the treatment of any one of the diseases or disorders mentioned in embodiment 32).
  • a further embodiment of the invention relates to the use of COMPOUND or a pharmaceutically acceptable salt thereof, especially of a crystalline form of COMPOUND according to any one of embodiments 1) to 21), for the preparation of a medicament intended for the treatment of any one of the diseases or disorders mentioned in embodiment 33).
  • a further embodiment of the invention relates to the use of COMPOUND or a pharmaceutically acceptable salt thereof, especially of a crystalline form of COMPOUND according to any one of embodiments 1) to 21), for the preparation of a medicament intended for the treatment of any one of the diseases or disorders mentioned in embodiment 34).
  • a further embodiment of the invention relates to a method for the treatment of any one of the diseases or disorders mentioned in embodiment 32), comprising administering to a patient an effective amount of COMPOUND or a pharmaceutically acceptable salt thereof, especially of a crystalline form of COMPOUND according to any one of embodiments 1) to 21), or of a pharmaceutical composition according to any one of embodiments 26) to 31).
  • a further embodiment of the invention relates to a method for the treatment of any one of the diseases or disorders mentioned in embodiment 33), comprising administering to a patient an effective amount of COMPOUND or a pharmaceutically acceptable salt thereof, especially of a crystalline form of COMPOUND according to any one of embodiments 1) to 21), or of a pharmaceutical composition according to any one of embodiments 26) to 31).
  • a further embodiment of the invention relates to a method for the treatment of any one of the diseases or disorders mentioned in embodiment 34), comprising administering to a patient an effective amount of COMPOUND or a pharmaceutically acceptable salt thereof, especially of a crystalline form of COMPOUND according to any one of embodiments 1) to 21), or of a pharmaceutical composition according to embodiments 26) to 31).
  • Yet another embodiment of the invention relates to the COMPOUND or a pharmaceutically acceptable salt thereof, especially a crystalline form of COMPOUND according to any one of embodiments 1) to 21), for use in the treatment of a disorder selected from the group consisting of chronic kidney disease (CKD), diabetes, diabetic nephropathy, diabetic retinopathy, diabetic vasculopathy, chronic heart failure and diastolic dysfunction.
  • CKD chronic kidney disease
  • diabetes diabetic nephropathy
  • diabetic retinopathy diabetic vasculopathy
  • chronic heart failure and diastolic dysfunction.
  • One sub-embodiment of embodiment 41) relates to the COMPOUND or a pharmaceutically acceptable salt thereof, especially a crystalline form of COMPOUND according to any one of embodiments 1) to 21), for use in the treatment of CKD, especially CKD of stages 1 to 4 as defined by the Kidney Disease Improving Global Outcomes (KDIGO) Guidelines (and notably CKD of stage 3), and in particular CKD (notably of these stages) caused by essential hypertension.
  • KDIGO Kidney Disease Improving Global Outcomes
  • Another sub-embodiment of embodiment 41) relates to the COMPOUND or a pharmaceutically acceptable salt thereof, especially a crystalline form of COMPOUND according to any one of embodiments 1) to 21), for use in the treatment of diabetes (that is, type 1 or type 2 diabetes).
  • Another sub-embodiment of embodiment 41) relates to the COMPOUND or a pharmaceutically acceptable salt thereof, especially a crystalline form of COMPOUND according to any one of embodiments 1) to 21), for use in the treatment of diabetic nephropathy.
  • Another sub-embodiment of embodiment 41) relates to the COMPOUND or a pharmaceutically acceptable salt thereof, especially a crystalline form of COMPOUND according to any one of embodiments 1) to 21), for use in the treatment of diabetic retinopathy.
  • Another sub-embodiment of embodiment 41) relates to the COMPOUND or a pharmaceutically acceptable salt thereof, especially a crystalline form of COMPOUND according to any one of embodiments 1) to 21), for use in the treatment of diabetic vasculopathy.
  • Another sub-embodiment of embodiment 41) relates to the COMPOUND or a pharmaceutically acceptable salt thereof, especially a crystalline form of COMPOUND according to any one of embodiments 1) to 21), for use in the treatment of chronic heart failure.
  • the chronic heart failure of sub-embodiment 47 will be heart failure with preserved ejection fraction.
  • the chronic heart failure of sub-embodiment 47 will be diastolic heart failure.
  • Another sub-embodiment of embodiment 41) relates to the COMPOUND or a pharmaceutically acceptable salt thereof, especially a crystalline form of COMPOUND according to any one of embodiments 1) to 21), for use in the treatment of diastolic dysfunction.
  • the COMPOUND or a pharmaceutically acceptable salt thereof [especially a crystalline form of COMPOUND according to any one of embodiments 1) to 21)] according to any one of embodiments 41) to 50) will be comprised in a pharmaceutical unit dosage form suitable for the oral administration of 2.5 to 100 mg (in particular 5 or 10 to 50 mg, notably 25 or 50 mg) per day of the COMPOUND (5-(4-bromo-phenyl)- 6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl ⁇ -sulfamide or of a pharmaceutically acceptable salt thereof.
  • the COMPOUND or pharmaceutically acceptable salt thereof [especially a crystalline form of COMPOUND according to any one of embodiments 1) to 21)] according to any one of embodiments 41) to 51) will be for use in combination with an Angiotensin Converting Enzyme (ACE) inhibitor, an Angiotensin Receptor Blocker (ARB) or a Calcium Channel Blocker (CCB), or with a pharmaceutically acceptable salt of one of these.
  • ACE Angiotensin Converting Enzyme
  • ARB Angiotensin Receptor Blocker
  • CB Calcium Channel Blocker
  • Angiotensin Converting Enzyme inhibitor or "ACE inhibitor” in particular means in the present application captopril, enalapril, ramipril, quinapril, perindopril, lisinopril, imidapril or cilazapril, or a pharmaceutically acceptable salt of one of these.
  • a preferred ACE inhibitor is enalapril or a pharmaceutically acceptable salt thereof.
  • “Angiotensin Receptor Blocker” or “ARB” in particular means in the present application valsartan, losartan, telmisartan, irbesartan, candesartan, olmesartan, azilsartan, or a pharmaceutically acceptable salt of one of these.
  • a preferred ARB is valsartan or a pharmaceutically acceptable salt thereof.
  • Calcium Channel Blocker in particular means in the present application amlodipine, aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine, isradipine, efonidipine, felodipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, pranidipine, verapamil or diltiazem or a pharmaceutically acceptable salt of one of these.
  • a preferred CCB is amlodipine or a pharmaceutically acceptable salt thereof.
  • the COMPOUND or a pharmaceutically acceptable salt thereof [especially a crystalline form of COMPOUND according to any one of embodiments 1) to 21)] according to any one of embodiments 41) to 51) can be for use in combination with an ACE inhibitor, an ARB, and/or a CCB.
  • the corresponding combined treatment may be effected simultaneously, separately, or over a period of time (especially simultaneously).
  • “Simultaneously”, when referring to an administration type, means in the present application that the administration type concerned consists in the administration of two or more active ingredients and/or treatments at approximately the same time; wherein it is understood that a simultaneous administration will lead to exposure of the subject to the two or more active ingredients and/or treatments at the same time.
  • said two or more active ingredients may be administered in a fixed dose combination, or in an equivalent non-fixed dose combination (e.g. by using two or more different pharmaceutical compositions to be administered by the same route of administration at approximately the same time), or by a non-fixed dose combination using two or more different routes of administration; wherein said administration leads to essentially simultaneous exposure of the subject to the two or more active ingredients and/or treatments.
  • the COMPOUND when used in combination with an ACE inhibitor, an ARB, and/or a CCB, the COMPOUND would possibly be used "simultaneously". Likewise, when used in combination with a diuretic, the COMPOUND would possibly be used "simultaneously”.
  • "Fixed dose combination" when referring to an administration type, means in the present application that the administration type concerned consists in the administration of one single pharmaceutical composition comprising the two or more active ingredients.
  • “Separately”, when referring to an administration type, means in the present application that the administration type concerned consists in the administration of two or more active ingredients and/or treatments at different points in time; wherein it is understood that a separate administration will lead to a treatment phase (e.g. at least 1 hour, notably at least 6 hours, especially at least 12 hours) where the subject is exposed to the two or more active ingredients and/or treatments at the same time; but a separate administration may also lead to a treatment phase where for a certain period of time (e.g. at least 12 hours, especially at least one day) the subject is exposed to only one of the two or more active ingredients and/or treatments.
  • a treatment phase e.g. at least 1 hour, notably at least 6 hours, especially at least 12 hours
  • a separate administration may also lead to a treatment phase where for a certain period of time (e.g. at least 12 hours, especially at least one day) the subject is exposed to only one of the two or more active ingredients and/or treatments.
  • Separate administration especially refers to situations wherein at least one of the active ingredients and/or treatments is given with a periodicity substantially different from daily (such as once or twice daily) administration (e.g. wherein one active ingredient and/or treatment is given e.g. once or twice a day, and another is given e.g. every other day, or once a week or at even longer distances).
  • administration “over a period of time” is meant in the present application the subsequent administration of two or more active ingredients and/or treatments at different times.
  • the term in particular refers to an administration method according to which the entire administration of one of the active ingredients and/or treatments is completed before the administration of the other / the others begins. In this way it is possible to administer one of the active ingredients and/or treatments for several months before administering the other active ingredient(s) and/or treatment(s).
  • the COMPOUND or pharmaceutically acceptable salt thereof [especially a crystalline form of COMPOUND according to any one of embodiments 1) to 21)] according to any one of embodiments 41) to 51) will be for use in combination with a diuretic (in particular for use in combination with hydrochlorothiazide (HCT)).
  • a diuretic in particular for use in combination with hydrochlorothiazide (HCT)
  • the COMPOUND or a pharmaceutically acceptable salt thereof [especially a crystalline form of COMPOUND according to any one of embodiments 1) to 21)] according to any one of embodiments 41) to 51) can be for use in combination with a diuretic (in particular for use in combination with HCT).
  • the corresponding combined treatment may be effected simultaneously, separately, or over a period of time (especially simultaneously), as defined hereabove.
  • Yet another embodiment of the invention relates to the use of the COMPOUND or of a pharmaceutically acceptable salt thereof [especially of a crystalline form of COMPOUND according to any one of embodiments 1) to 21)], for the manufacture of a medicament for use in the treatment of a disorder selected from the group consisting of chronic kidney disease (CKD), diabetes, diabetic nephropathy, diabetic retinopathy, diabetic vasculopathy, chronic heart failure and diastolic dysfunction.
  • CKD chronic kidney disease
  • diabetes diabetic nephropathy
  • diabetic retinopathy diabetic vasculopathy
  • chronic heart failure and diastolic dysfunction.
  • One sub-embodiment of embodiment 54) relates to the use according to embodiment 54) which is for the manufacture of a medicament for use in the treatment of
  • CKD especially CKD of stages 1 to 4 as defined by the Kidney Disease Improving Global Outcomes (KDIGO) Guidelines (and notably CKD of stage 3), and in particular CKD (notably of these stages) caused by essential hypertension.
  • KDIGO Kidney Disease Improving Global Outcomes
  • Another sub-embodiment of embodiment 54) relates to the use according to embodiment 54) which is for the manufacture of a medicament for use in the treatment of diabetes (that is, type 1 or type 2 diabetes).
  • Another sub-embodiment of embodiment 54) relates to the use according to embodiment 54) which is for the manufacture of a medicament for use in the treatment of diabetic nephropathy.
  • embodiment 54 Another sub-embodiment of embodiment 54) relates to the use according to embodiment 54) which is for the manufacture of a medicament for use in the treatment of diabetic retinopathy.
  • embodiment 54 Another sub-embodiment of embodiment 54) relates to the use according to embodiment 54) which is for the manufacture of a medicament for use in the treatment of diabetic vasculopathy.
  • embodiment 54 Another sub-embodiment of embodiment 54) relates to the use according to embodiment 54) which is for the manufacture of a medicament for use in the treatment of chronic heart failure.
  • the chronic heart failure of sub-embodiment 60 will be heart failure with preserved ejection fraction.
  • the chronic heart failure of sub-embodiment 60 will be diastolic heart failure.
  • FIG. 63 Another sub-embodiment of embodiment 54) relates to the use according to embodiment 54) which is for the manufacture of a medicament for use in the treatment of diastolic dysfunction.
  • the use according to any one of embodiments 54) to 63) will be such that it is for the manufacture of a pharmaceutical unit dosage form suitable for the oral administration of 2.5 to 100 mg (in particular 5 or 10 to 50 mg, notably 25 or 50 mg) per day of the COMPOUND or of a pharmaceutically acceptable salt thereof [especially of a crystalline form of COMPOUND according to any one of embodiments 1) to 21)].
  • the use according to any one of embodiments 54) to 64) will be for the manufacture of a medicament for use in combination with an Angiotensin Converting Enzyme (ACE) inhibitor, an Angiotensin Receptor Blocker (ARB) or a Calcium Channel Blocker (CCB) or with a pharmaceutically acceptable salt of one of these.
  • ACE Angiotensin Converting Enzyme
  • ARB Angiotensin Receptor Blocker
  • CCB Calcium Channel Blocker
  • any one of embodiments 54) to 64) can be for the manufacture of a medicament for use in combination with an ACE inhibitor, an ARB or a CCB or with a pharmaceutically acceptable salt of one of these.
  • the corresponding combined treatment may be effected simultaneously, separately, or over a period of time (especially simultaneously).
  • the use according to any one of embodiments 54) to 64) will be for the manufacture of a medicament for use in combination with a diuretic (in particular for the manufacture of a medicament for use in combination with hydrochlorothiazide (HCT)).
  • a diuretic in particular for the manufacture of a medicament for use in combination with hydrochlorothiazide (HCT)
  • any one of embodiments 54) to 64) can be for the manufacture of a medicament for use in combination with a diuretic (in particular for the manufacture of a medicament for use in combination with HCT).
  • the corresponding combined treatment may be effected simultaneously, separately, or over a period of time (especially simultaneously), as defined hereabove.
  • Yet another embodiment of the invention relates to a method for treating a disorder selected from the group consisting of chronic kidney disease (CKD), diabetes, diabetic nephropathy, diabetic retinopathy, diabetic vasculopathy, chronic heart failure and diastolic dysfunction in a patient, said method comprising the administration of a therapeutically effective amount of the COMPOUND or of a pharmaceutically acceptable salt thereof [especially of a crystalline form of COMPOUND according to any one of embodiments 1) to 21)], to a patient in need thereof.
  • CKD chronic kidney disease
  • CKD chronic kidney disease
  • diabetes diabetic nephropathy, diabetic retinopathy, diabetic vasculopathy, chronic heart failure and diastolic dysfunction
  • CKD chronic kidney disease
  • a pharmaceutically acceptable salt thereof especially of a crystalline form of COMPOUND according to any one of embodiments 1) to 21
  • One sub-embodiment of embodiment 67) relates to the method according to embodiment 67) which is for treating CKD in a patient, especially CKD of stages 1 to 4 as defined by the Kidney Disease Improving Global Outcomes (KDIGO) Guidelines (and notably CKD of stage 3), and in particular CKD (notably of these stages) caused by essential hypertension.
  • KDIGO Kidney Disease Improving Global Outcomes
  • Another sub-embodiment of embodiment 67) relates to the method according to embodiment 67) which is for treating diabetes (that is, type 1 or type 2 diabetes).
  • Another sub-embodiment of embodiment 67) relates to the method according to embodiment 67) which is for treating diabetic nephropathy.
  • Another sub-embodiment of embodiment 67) relates to the method according to embodiment 67) which is for treating diabetic retinopathy.
  • Another sub-embodiment of embodiment 67) relates to the method according to embodiment 67) which is for treating diabetic vasculopathy.
  • Another sub-embodiment of embodiment 67) relates to the method according to embodiment 67) which is for treating chronic heart failure.
  • the chronic heart failure of sub-embodiment 73 will be heart failure with preserved ejection fraction.
  • the chronic heart failure of sub-embodiment 73 will be diastolic heart failure.
  • Another sub-embodiment of embodiment 67) relates to the method according to embodiment 67) which is for treating diastolic dysfunction.
  • the method according to any one of embodiments 67) to 76) will be such that a dose of 2.5 to 100 mg (in particular 5 or 10 to 50 mg, notably 25 or 50 mg) per day of the COMPOUND or of a pharmaceutically acceptable salt thereof [especially of a crystalline form of COMPOUND according to any one of embodiments 1) to 21)] is administered orally to a patient in need thereof.
  • the method according to any one of embodiments 67) to 77) will such that a therapeutically effective amount of the COMPOUND or of a pharmaceutically acceptable salt thereof [especially of a crystalline form of COMPOUND according to any one of embodiments 1) to 21)] is administered in combination with a therapeutically effective amount of an Angiotensin Converting Enzyme (ACE) inhibitor, an Angiotensin Receptor Blocker (ARB) or a Calcium Channel Blocker (CCB) or of a pharmaceutically acceptable salt of one of these.
  • ACE Angiotensin Converting Enzyme
  • ARB Angiotensin Receptor Blocker
  • CCB Calcium Channel Blocker
  • the method according to any one of embodiments 67) to 77) can be such that a therapeutically effective amount of the COMPOUND or of a pharmaceutically acceptable salt thereof [especially of a crystalline form of COMPOUND according to any one of embodiments 1) to 21)] is administered in combination with a therapeutically effective amount of an ACE inhibitor, an ARB or a CCB or of a pharmaceutically acceptable salt of one of these.
  • the corresponding combined treatment may be effected simultaneously, separately, or over a period of time (especially simultaneously).
  • the method according to any one of embodiments 67) to 77) will such that a therapeutically effective amount of the COMPOUND or of a pharmaceutically acceptable salt thereof [especially of a crystalline form of COMPOUND according to any one of embodiments 1) to 21)] is administered in combination with a therapeutically effective amount of a diuretic (in particular in combination with a therapeutically effective amount of hydrochlorothiazide (HCT)).
  • a therapeutically effective amount of the COMPOUND or of a pharmaceutically acceptable salt thereof especially of a crystalline form of COMPOUND according to any one of embodiments 1) to 21)
  • the method according to any one of embodiments 67) to 77) can be such that a therapeutically effective amount of the COMPOUND or of a pharmaceutically acceptable salt thereof [especially of a crystalline form of COMPOUND according to any one of embodiments 1) to 21)] is administered in combination with a therapeutically effective amount of a diuretic (in particular in combination with a therapeutically effective amount of HCT).
  • the corresponding combined treatment may be effected simultaneously, separately, or over a period of time (especially simultaneously).
  • X-ray powder diffraction patterns were collected on a Bruker D8 Advance X-ray diffractometer equipped with a Lynxeye detector operated with CuKa-radiation in reflection mode (coupled two Theta/Theta). Typically, the X-ray tube was run at of 40kV/40mA. A step size of 0.02° (2 ⁇ ) and a step time of 76.8 sec over a scanning range of 3 - 50° in 2 ⁇ were applied. The divergence slit was set to fixed 0.3. Powders were slightly pressed into a silicon single crystal sample holder with depth of 0.5 mm and samples were rotated in their own plane during the measurement.
  • Measurements are performed on a multi sample instrument SPS-100n ( Pramp Messtechnik, Ulm, Germany) operated in stepping mode at 25°C.
  • the sample is allowed to equilibrate at 40% RH before starting a pre-defined humidity program (40-0-95-0-95-40% RH, steps of 5% ARH and with a maximal equilibration time of 24 hours per step are applied.
  • About 20 to 30 mg of each sample is used.
  • hygroscopic classification is done according to the European Pharmacopeia Technical Guide (1999, page 86), e.g., slightly hygroscopic: increase in mass is less than 2% and equal to or greater than 0.2% mass/mass; hygroscopic: increase in mass is less than 15% and equal to or greater than 2% mass/mass.
  • the mass change between 40% relative humidity and 80% relative humidity in the first adsorption scan is considered.
  • DSC Differential scanning calorimetry
  • DSC data are collected on a Mettler Toledo STARe System (DSC822e module, measuring cell with ceramic sensor and STAR software version 9.20) equipped with a 34-position auto-sampler.
  • the instrument is calibrated for energy and temperature using certified indium.
  • 1-5 mg of each sample, in an automatically pierced aluminium pan, is heated at 10°C min-1, unless stated otherwise, from -20°C to 280°C.
  • a nitrogen purge at 20 mL min-1 is maintained over the sample. Peak temperatures are reported for melting points.
  • TGA data are collected on a Mettler Toledo STARe System (TGA851e module and STAR software version 9.20) equipped with a 34 position auto-sampler. Typically about 5 mg of a sample, in an automatically pierced aluminium pan, is heated at 10°C min 1 , unless stated otherwise, from 30°C to 250°C. A nitrogen purge at 10 mL min-1 is maintained over the sample.
  • Example 1 Form A;
  • the solid was slurried in water (1000 mL, 10 vol.) at rt for 3 h.
  • the solid was filtered off and slurried a second time in water (1000 mL, 10 vol.) at rt for 3 h.
  • the pure product was dried in vacuum at 40°C to afford ⁇ 5-(4-bromo-phenyl)-6-[2-(5-bromo- pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl ⁇ -sulfamide as a white to off-white solid (75 g, 65% yield, XRPD pattern form A).
  • Example 8 Form L iEtOH solvate of the COMPOUND
  • Tablets containing each 50 mg of COMPOUND can be prepared using a wet granulation rocess.
  • the tablet composition is the following:
  • COMPOUND in crystalline Form A (as described herein) will be used for making the tablets.
  • Example 10 ACT-132577 tablets
  • Example 9 The tablets of Example 9 can be coated with a layer of Aquapolish ® white MS or Aquapolish ® white PVA (coating manufacturer: Bioground).
  • Example 11 ACT-132577 tablets
  • Tablets containing each 50 mg of COMPOUND can be prepared using a wet granulation process.
  • the tablet composition is the following:
  • COMPOUND in crystalline Form A (as described herein) will be used for making the tablets.
  • Example 1 1 can be coated with a layer of Aquapolish ® white MS or Aquapolish ® white PVA (coating manufacturer: Bioground).
  • Tablets containing each 12.5 mg of COMPOUND can be prepared using a wet granulation process.
  • the tablet composition is the following:
  • COMPOUND in crystalline Form A (as described herein) will be used for making the tablets.
  • Example 14 ACT-132577 tablets
  • Example 13 can be coated with a layer of Aquapolish ® white MS or Aquapolish ® white PVA (coating manufacturer: Bioground).
  • Example 15 ACT-132577 tablets
  • Tablets containing each 12.5 mg of COMPOUND can be prepared using a wet granulation process.
  • the tablet composition is the following:
  • COMPOUND in crystalline Form A (as described herein) will be used for making the tablets.
  • Example 16 ACT-132577 tablets
  • Example 15 can be coated with a layer of Aquapolish ® white MS or Aquapolish ® white PVA (coating manufacturer: Bioground). Properties of the crystalline forms
  • a sample of Form A crystals of the COMPOUND (as obtained according to Example 1 above) has been stored at a temperature of 20-25°C at 92% relative humidity for 2 months. X-ray powder diffraction performed on that sample at the end of the 2 months showed that the sample was still consisting only in Form A crystals of the COMPOUND. The same result was obtained after storage for 8 weeks under the above coditions. HPLC control of the sample after 8 weeks storage revealed no significant change in peak area%, i.e. no significant degradation was observed under such conditions.
  • a sample of Form B crystals of a dichloromethane solvate of the COMPOUND (as obtained according to Example 2 above) has been stored in a closed vial (20 mg of Form B crystals being placed in a closed 4 mL vial) at a temperature of 20-25°C for about 3 weeks. X-ray powder diffraction performed on that sample at the end of the 3 weeks showed that the Form B crystals were transformed into Form A crystals of the COMPOUND.
  • a sample of Form K crystals of a dimethylsulfoxide solvate of the COMPOUND (as obtained according to Example 7 above) has been stored in a closed vial (20 mg of Form K crystals being placed in a closed 4 mL vial) at a temperature of 20-25°C for about 3 weeks. X-ray powder diffraction performed on that sample at the end of the 3 weeks showed that the Form K crystals were transformed into Form A crystals of the COMPOUND.
  • Form A of COMPOUND melts and decomposes concomitantly.
  • DSC an endothermic/exothermic signal is observed, with a peak of the endotherm observed at about 159°C.
  • Form C of COMPOUND melts and decomposes concomitantly.
  • DSC an endothermic/exothermic signal is observed, with a peak of the endotherm observed at about 153°C.
  • Form A e.g. as obtained from Example 1 is considered to be non-hygroscopic as determined by gravimetric vapor sorption (GVS) (see Figure 19).
  • VGS gravimetric vapor sorption
  • Form C e.g. as obtained from Example 3 is considered to be slightly hygroscopic as determined by gravimetric vapor sorption (GVS) (see Figure 20).
  • MAP mean arterial blood pressure
  • HR heart rate
  • Elevated blood pressure is induced in Dahl-S rats by providing 1% sodium chloride in drinking water.
  • Groups of 6-7 Dahl-S rats were used for the vehicle (7.5% gelatin aquous solution) and each dose of COMPOUND tested (0.3, 1, 3, 10, 30, 100, and 300 mg/kg).
  • Effects of COMPOUND on HR and MAP were calculated for individual animals relative to the 24 h period before administering.
  • the results obtained regarding MAP are summarised in Figure 9 (data are presented as mean ⁇ standard error of the mean).
  • a dose of 10 mg/kg COMPOUND decreased MAP by 19 ⁇ 4 mm Hg in Dahl-S rats.
  • HR was not affected.
  • EXAMPLE B acute effects of COMPOUND in deoxycorticosterone acetate salt rats:
  • MAP mean arterial blood pressure
  • HR heart rate
  • EXAMPLE C acute effects of COMPOUND in spontaneaously hypertensive rats: The acute effects of COMPOUND on blood pressure, in particular on mean arterial blood pressure (hereafter "MAP”), and heart rate (hereafter “HR”) were evaluated by means of telemetry in conscious, male spontaneaously hypertensive rats (hereafter "SHRs” - see details about this model in Atanur et al, Genome Res. (2010), 20, 791-803).
  • MAP mean arterial blood pressure
  • HR heart rate
  • EXAMPLE D acute effects of COMPOUND, alone or in combination with valsartan, in spontaneaously hypertensive rats:
  • EXAMPLE E acute effects of COMPOUND, alone or in combination with valsartan, in deoxycorticosterone acetate salt rats:
  • EXAMPLE F acute effects of COMPOUND, alone or in combination with enalapril, in spontaneaously hypertensive rats:
  • EXAMPLE G acute effects of COMPOUND, alone or in combination with amlodipine, in deoxycorticosterone acetate salt rats:
  • EXAMPLE H chronic effects of COMPOUND in deoxycorticosterone acetate salt rats:
  • DOCA 0 2w represents DOCA-salt rats sacrified just before initiation of treatment with COMPOUND
  • ⁇ ⁇ the "*" symbol in represents a statistical significance factor p ⁇ 0.05 when using a one way ANOVA followed by a Newmal-Keuls multiple comparisons post-hoc test.
  • COMPOUND chronic oral administration of COMPOUND to DOCA-salt rats dose-dependently increased renal blood flow and decreased renal vascular resistance.
  • COMPOUND also tended to decrease left ventricular hypertrophy, as suggested by the dose-dependent decrease in plasma concentrations of N-terminal pro-brain natriuretic peptide (NTproBNP).
  • NproBNP N-terminal pro-brain natriuretic peptide
  • EXAMPLE I effects of COMPOUND, alone or in combination with an ACE inhibitor or an ARB, in animal models of diabetes:
  • COMPOUND can be assessed in diabetic rodent models (in this regard, see the models described in the following references: Sen et al, Life Set (2012), 91(13-14), 658-668; Janiak et al, Eur. J. Pharmacol. (2006), 534, 271-279; and Iglarz et al, J. Pharmacol. Exp. Ther. (2008), 327(3), 736-745).
  • End organ damage includes: vascular function, renal function (e.g. proteinuria), cardiac function and remodelling and any other target organ affected by diabetes (e.g. the eye).
  • haematocrit A decrease in haematocrit (Hct) or haemoglobin occurs secondary to an increase in plasma volume and can be used as a marker of fluid retention.
  • a single oral dose of aprocitentan (1-30 mg/kg) or vehicle (gelatin) was administered by gavage to male Wistar rats. Twenty- four hours after administration, sublingual blood was sampled under isoflurane-induced anesthesia. Haematocrit was measured using a hematology analyser. COMPOUND did not impact on haematocrit (Hct) suggesting low liability on fluid retention ( Figure 18).
  • COMPARISON EXAMPLE 1 acute effects of spironolactone used in combination with valsartan in spontaneaously hypertensive rats:
  • MAP mean arterial blood pressure
  • HR heart rate
  • COMPARISON EXAMPLE 2 acute effects of spironolactone used in combination with valsartan in deoxycorticosterone acetate salt rats:
  • MAP mean arterial blood pressure
  • HR heart rate
  • COMPARISON EXAMPLE 3 acute effects of spironolactone used in combination with enalapril in spontaneaously hypertensive rats:
  • MAP mean arterial blood pressure
  • HR heart rate

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Abstract

La présente invention concerne de nouvelles formes cristallines du {5-(4-bromo-phényl)-6-[2-(5-bromo-pyrimidine-2-yloxy)-éthoxy]-pyrimidine-4-yl}-sulfamide, des procédés pour leur préparation, des compositions pharmaceutiques comprenant lesdites formes cristallines, des compositions pharmaceutiques préparées à partir de telles formes cristallines, et leur utilisation en tant qu'antagonistes du récepteur de l'endothéline. Elle concerne également de nouvelles utilisations du {5-(4-bromo-phényl)-6-[2-(5-bromo-pyrimidine-2-yloxy)-éthoxy]-pyrimidine-4-yl}-sulfamide, seul ou en association avec d'autres principes actifs ou agents thérapeutiques.
PCT/EP2018/054627 2017-02-27 2018-02-26 Formes cristallines du dérivé 4-pyrimidinesulfamide aprocitentan WO2018154101A1 (fr)

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BR112019017644-6A BR112019017644A2 (pt) 2017-02-27 2018-02-26 Forma cristalina de {5-(4-bromo-fenil)-6-[2-(5-bromo-pirimidina-2-iloxi)-etoxi]-pirimidina-4-il}-sulfamida, composição farmacêutica, uso de uma forma cristalina do composto {5-(4-bromo-fenil)-6-[2-(5-bromo-pirimidina-2-iloxi)-etoxi]-pirimidina-4-il}-sulfamida, e, método de tratamento
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US20200061061A1 (en) 2017-02-27 2020-02-27 Idorsia Pharmaceuticals Ltd Combinations of a 4-pyrimidinesulfamide derivative with active ingredients for the treatment of endothelin related diseases
US11174247B2 (en) 2017-02-27 2021-11-16 Idorsia Pharmaceuticals Ltd Combinations of a 4-pyrimidinesulfamide derivative with active ingredients for the treatment of endothelin related diseases
US11787782B2 (en) 2017-02-27 2023-10-17 Idorsia Pharmaceuticals Ltd Combinations of a 4-pyrimidinesulfamide derivative with active ingredients for the treatment of endothelin related diseases
US12144811B2 (en) 2017-11-30 2024-11-19 Idorsia Pharmaceuticals Ltd Combination of a 4-pyrimidinesulfamide derivative with an SGLT-2 inhibitor for the treatment of endothelin related diseases
CN112569357A (zh) * 2019-09-30 2021-03-30 深圳奥萨制药有限公司 双重内皮素受体拮抗剂与利尿剂的组合物
WO2021088645A1 (fr) 2019-11-07 2021-05-14 苏州科睿思制药有限公司 Forme cristalline d'aprocitentan, son procédé de préparation et son utilisation
WO2023227490A1 (fr) 2022-05-22 2023-11-30 Idorsia Pharmaceuticals Ltd Aprocitentan pour le traitement de l'hypertension
WO2023227721A1 (fr) 2022-05-25 2023-11-30 Idorsia Pharmaceuticals Ltd Formes cristallines de (5-(4-bromophényl)-6-(2- ((5-bromopyrimidin-2-yl) oxy) éthoxy) pyrimidin-4-yl) (sulfamoyl) amide de sodium

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